The immune system is a self-defensive structure mainly consisting of lymphatic organs (thymus glands, lymph nodes, spleen, tonsils), lymphatic tissues within other organs, lymphocytes throughout the body, antigen presenting cell, and the like. The immune system also includes other leucocytes in blood, and plasma cells and mast cells in connective tissues. The key components of the immune system are lymphocytes, which endue the immune system with the capability of recognition and memory. The lymphocytes travel throughout the body via blood and lymph, migrating from one lymphatic organ or tissue to another lymphatic organ or tissue, and connecting the lymphatic organs or tissues scattered throughout the body to form a functional entirety. T cells and B cells are the most important immunocytes in human bodies. The normal functioning of each component of the immune system provides the guarantee for the relative stability of the body immune functions, and any deficiencies or hyperactions of the component would cause damage to the body.
The components of immune system reach the whole body widely and complicatedly, particularly with the continuous production, circulation, and regeneration of the immune cells and immune molecules. The immune system possesses a great recognizability, which can precisely detect a foreign substance and distinguish it from human's own healthy tissue in order to maintain body's relative stability. Simultaneously, the immune system can accept, transfer, enlarge, depot, and memorize the related immune information, and provide positive or negative responses and regulate the responsibility to the immune information. However, the malfunctions of the immune system are disadvantageous to human body: human's abnormal recognizability easily results in allergy phenomenon, or causes iterative infections conversely; the abnormal stabilizing ability may induce the immune system to give responses to self-cells, which gives rise to autoimmune diseases.
Immunosuppressive agent is a type of new medicine category, which developed from the foundation of the research on neoplasm-chemotherapy, organ transplantation, immunopathology, and clinical immunology, etc. It possesses immunosuppressive effects which inhibits abnormal immune responses, and is generally used in the therapy of organ transplant rejection and autoimmune diseases.
Cyclophosphamide (CTX) was firstly applied to clinical practice, which was discovered to be hydroxylated by hepatocyte microsomes to generate the alkylated metabolite behaving potent and lasting immune functions. It is utilized as an immunosuppressive agent in the treatment of nephritic syndrome, systemic lupus erythematosus, and rheumatoid arthritis and so on by means of killing the immune cells and influencing every phase of the immunologic processes. But it is restricted because of the relatively obvious side effects.
Glucocorticoid is the most commonly used immunosuppressive agent in clinic nowadays, which can inhibit body's immune responses by inhibiting the phagocytic functions of macrophages, reducing the production of an auto-antibody against an auto-antigen. It is generally used for treating acute inflammation, allergy, organ transplant rejection, and some autoimmune diseases, etc.
Azathioprine is an immunosuppressive agent, which inhibits T cells and B cells. Azathioprine has been an effective drug for preventing organ transplant rejection for years, and is also used for various autoimmune diseases.
Cyclosporine A (CsA) is a cytokine synthesis inhibitor, which inhibits gene transcription of T cells cytokine, interrupts T cells production, and interferes activation of T cells. It belongs to an inhibitor of T cells activation at early phase, which interrupts T cells activations at phase G0/G1 (G0, G1 and S are different phases of a cell cycle). Since 1980s, CsA has been successively applied to various organ and tissue transplantations, and achieved abroad successes, which opened a new era for organ transplantations.
FK506 is another kind of binder subsequent to the development of CsA, which can prevent various transplant rejections, especially is useful in liver transplantation. FK506 has immunosuppressive effect 10˜100 times stronger than CsA, and has lower acute or chronic rejection rate, lower infection rate, lower dosage of hormone, and less adverse reaction than CsA. FK506 can reverse acute rejection and is expected to replace CsA to be the first choice as an immunosuppressive agent after an organ transplant.
Rapamycin (RPM), firstly used for anti-transplant rejection, can effectively prevent rejection reaction. Rapamycin is able to decrease the acute rejection rate in combination with other drugs. It can specifically inhibit the phosphorylation and activity of protein kinase to inhibit cytokine induced protein and DNA synthesis. It is a late stage T cells and B cells activation inhibitor. RPM, as a novel immunosuppressant, not only can inhibit the immune cells, but also can hinder the proliferation and transmigration of vascular smooth muscle to reduce rejection reaction.
Mycophenolate mofetil, approved by American FDA, was applied in clinical rapidly. It has potent curative effects and a high selective effect on proliferative lymphocytes, as well as can prevent the formation of antibody through direct inhibition of B cells proliferation.
Due to the restrictions of selectivity and specificity, the above mentioned immunosuppressive agents will inevitably damage immune defense capacity of the patients when receiving the treatment, resulting in the descent anti-infection ability of patients, the increasing risk of malignant lesions, the injury of hematopoietic system, immune system, liver, kidney and gastrointestinal function, neural and endocrine function disorder, and inducing some allergic reactions, etc. For instance, cyclophosphamide may cause hair loss, and induce hemorrhagic cystitis, such as frequent micturition, urodynia, hematuria, and proteinuria; glucocorticoids may aggravate or induce infection, induce gastric ulcer, combined with hemorrhage and perforation, provoke metabolic disorders, raise blood pressure, blood glucose, and blood fat, cause osteoporosis, and evoke adverse reaction of insomnia by exciting central nervous system; azathioprine can cause cholestasis and hepatocellular damage; MTX induce canal damage symptoms, such as oral cavity ulcer, bloody stool, and so on, and can cause teratism and stillbirth; cyclosporin is toxic to kidney, liver and nervous system, and can lead to high blood pressure, secondary infection and onset of tumor; FK506 also has renal toxicity, even more than CsA in neurotoxicity, and causes damages on the islet β2 cells that induces diabetes; rapamycin can elicit leukopenia, thrombocytopenia and hyperlipidemia; mycophenolate mofetil can cause vomiting, diarrhea and other gastrointestinal symptoms, leukopenia, sepsis and high blood uric acid, hyperkalemia, myalgia or sleepiness, etc.
Sphingosine-1-phosphate enzyme receptor antagonist FTY720 and sphingosine (a kind of endogenous hemolytic lipid) have some structural similarities. Sphingosine is phosphorylated to form sphingosine-1-phosphatek enzyme, a homologous series ligands of its receptor family, induced by sphingosine enzyme. Activation of the receptor leads to the following physiological activities: cells differentiation, growth and survival, and regulations of cytoskeletal recombinant that can change adhesion and morphology of cells. In the normal immune responses, the proliferation of T lymphocytes and B lymphocytes is taken place in lymph nodes. They down-regulate the sphingosine-1-phosphate receptor expression when they are in the lymph nodes. Once their activation and proliferation are completed, they will up-regulate the number of sphingosine-1-phosphate receptor on cell surface, which allowed them to leave the lymph nodes. Lymphocyte sphingosine-1-phosphate enzyme receptors bind to their ligands resulting in the down-regulation of sphingosine-1-phosphate enzyme, and thus losing the function of separating from the lymph nodes. To the end, lymphocytes will adhere to the lymph nodes (1, 2, 3). Traditional immunosuppressive agents such as cyclosporin have the action mechanism of inhibiting activation of T lymphocytes and B lymphocytes. In contrast, sphingosine-1-phosphate enzyme receptor antagonist achieves the purpose by means of limiting lymphocytes within the lymph system other than impairing the immune responses by lymphocytes inactivation. Sphingosine-1-phosphate enzyme receptor antagonist can be used for the treatment of various transplant rejections and immune inflammatory diseases.
Sphingosine-1-phosphate enzyme receptor antagonist FTY720 was successfully developed by Novartis (Novartis), and conducted clinical trials on multiple sclerosis and transplant patients in America and Europe (4, 5), and has gotten through a phase II clinical trial. However, FTY720 acts on not only sphingosine-1-phosphate enzyme receptor-1 (S1P1), but sphingosine-1-phosphate enzyme receptor-3 (S1P3), therefore, it can cause side effects such as bradycardia (6).